Dialkylaminoalkoxyphenylethanol esters



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United States Patent DIALKYLAMINOALKOXYPHENYLETHANOL ESTERS Seymour L. Shapiro, Hastings on Hudson, Louis Freedman, Bronxville, and Harold Soloway, Yonkers, N.Y., assignors to US. Vitamin & Pharmaceutical Corporation, New York, N.Y., a corporation of Delaware No Drawing. Application April 9, 1958 Serial No. 727,258

This invention relates to aryl and arylalkyl esters of B-dialkylaminoalkoxy-a-phenylethanols. More specifically, this invention is concerned with compounds of the formula cinnamoyl group C H CH=CHCO. Y is an alkylene linking element containing 2-3 carbon atoms such as ethylene, propylene and trimethylene.

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2 EVALUATION AS ANESTHETICS The compounds of this invention were evaluated by the method of Chance and Lobstein, J. Pharmacol., 82, 203 (1944), for determining the median eliective dose of a local anesthetic when applied to the cornea of a guinea pig eye.

A known concentration of solution of the local anesthetic is applied to both eyes of a guinea pig and the eyes kept bathed with this solution for two minutes. The eyes are then blotted to remove excess solution.

Five minutes later, the eyes are tested for the anesthetic effect. The hair is pressed against the center of the cornea so that the hair is bent to about the same extent at each application. The hair is applied 10 times to each eye, and the process repeated 5 times for the test (total of 100 prods). The result is reported thus: 100 minus number of blinks=percent anesthesia.

Varying concentrations of the anesthetic agent are used and the percent anesthesia is plotted against concentra' tion. The results are expressed as the ED in mg./ml. which is the quantity of compound per milliliter of solution required to effect 50% anesthesia as established from the plot of concentration vs. percent anesthesia.

The toxicity of the individual compounds was established by administration subcutaneously (s.c.) to mice, in terms of the minimum dose required to be lethal to mice and expressed as LD in milligrams of compound per kilogram of mouse.

The therapeutic index was then calculated by dividing the LD by the ED the result being a single figure embracing the anesthetic efiectiveness of the compound and its inherent toxicity.

The results are shown in Table I. It will be noted that the compounds show therapeutic indexes of 230- 9400 as compared to the index of 13 found for procaine, the standard local anesthetic, in comparative tests.

Table 1.Anestheric potency of esters of p-dialkylaminoethoxy-a-substituted phenylezhanols The compounds of this invention are particularly use- 40 ful as anesthetics and the invention will be illustrated by description in connection with such use. N-Y-O-CHr-CH@ Our esters show a very large improvement in the therapeutic index over conventional anesthetics. Thus, we have raised the therapeutic index of 13 found for procaine T in our test method to as much as 300-9400 for our compounds under comparable conditions. One feature of our R compounds, therefore, is their relative freedom from toxicity coupled with unusual efiectiveness in anesthetic R Ra Ra R4 Y EDn L mln Therapeutic mg.lml. mg. g Index (CHrlsCH- OH,- H H (OH:): 0. 68 300 440 CgHs- 01H;- H H -(CHz): 0. 2 1. 000 5, 000 CrHr- CrHsp-OHP H (CHm- 0. 66 750 1, n-C Hr n-ChHe- H H (CH2):- 2. 6 750 288 (C r i H H (CHr)2 0.08 750 9, 400 -(0H- H 7 H (CHz): 4.3 1,000 230 CzHr- CzHs- H p-CH-r- -(CH2)2 0. 66 250 380 cnn- 01H,- H o-orno- (c H2)2- 0. 4 200 600 cr r- Cl t- H D-CHsO- -(CHz)2- 0. 05 2, 500 cnn- 0:11P- H p-Cl (cHm- 0. 26 750 2, 880 CsHs- 0:11P H -(CIIa)r- 0. 28 750 2, 680 Procalne (control). 15.0 200 e The esteriiying group is clnnamoyl rather than benzoyl (this is the product of Example 6).

action. Thus, some of our esters exhibit toxicities as low as one fifth that of procaine. Coupled with this safety factor of decreased toxicity is the high potency as anesthetics, which in individual cases is 5-240 times that of procaine. This desirable combination of normally opposed properties will be more clearly reflected in the pharmacological studies reported in Table I.

The compounds of this invention are bases, and as such form salts with inorganic or organic acids, and the compounds are suitably used in the form of their salts with inorganic acids such as hydrochloric, hydrobromic, sulfuric and the like, and such organic acids as acetic acid, butyric acid, pantothenic acid, theophylline, penicillin and the like.

A horse hair mounted on a glass rod is used..

Salts. of the esters are readily prepared by the usual technique, as for example, by neutralizing our esters which are bases, by hydrochloric, hydrobromic, phosphoric, sulfuric, succinic, acetic, or tartaric acid, and other non-toxic acidin a suitable'solvent such as alcohol, water, ether or benzene. Thesalts form directly and are collected on a filter or recovered by evaporation.

. Quaternary salts are prepared by reaction of the basic esters with such quaternizing agents as. methyl iodide, methyl sulfate, methyl toluene-sulfonate, ethyl bromide, benzyl bromide, allyl bromide and ethyl bromoacetate.

Thesecompounds of this invention are racemic mixtures of the dl forms and the'invention encompasses the individual d and 1 forms, separable by techniques familiar to those skilled in the art.

In the preparation of the compounds of this invention, fi-dialltylamino-alkoxy-a-phenylethanols (I) are esterified by reaction with the appropriately substituted hen-- zoyl chloride or cinnamoyl chloride in an organic solvent such as benzene, toluene, ether or acetonitrile which is inert to the reactants, and in the presence of'an acid acceptor. The acid acceptor function can also be served by the dialkylaminoalkyl component of the reactant alcohol, or. the resultant product which is acorresponding basic ester. The reaction proceeds satisfactorily in some instances at room temperature, whereas other esterifications are desirably conducted at the reflux temperature of the solvent.

The required amino alcohols (I) are prepared by condensation of dialkylaminoalkanols with styrene oxide, or p-methylstyrene oxide in the presence of an alkali metal catalyst according to the following equation:

After a suitable reaction period under reflux, the amino alcohol (I) is separated. In the course of the reaction, non-basic high-boiling side products, as yet unidentified, are formed, and after the condensation is completed,the basic components are separated when necessary into an aqueous phase as their hydrochloride salts, the non-basic side products are extracted with ether, the aqueous phase is then made basic, extracted with ether, and the desired amino alcohol (I) obtained by fractional distillation.

much the same manner with the selection of starting materials required for the production of any particular desired specific compound. Temperatures where shown are in C.

EXAMPLE 1 .-2- 2- N-METHYL-N-I-PROPYLAMINO] ETHOXY) -1PHENYLETHANOL Sodium, 0;1 g. (0.005 mole), was added in small portions to 46.8 g. (0.4 mole) of N-methyl-N-isopropylaminoethanol' while stirring. After solution was complete, the temperature was raised to and 24.0 g. (0.2 mole) of styrene oxide added over a period of 1.5 hours. Stirring was continued at this temperature for an additional 5 hours.

On distillation, 23.5 g. of N-methyl-N-isopropylaminoethanol was collected, boiling at 72 at 30 mm., followed by 28 g. (60%) of product distilling at -128 at 0.35 mm.

Analysis.Calcd; forC H- NO C, 70.9; H, 9.8; N, 5.9. Found: C, 71.1; H, 9.4; N, 5.6.

A hydrochloride was prepared and recrystallized first from methyl ethyl ketone, then from isopropyl alcohol and isopropyl ether mixture, melting at 133-137".

Analysis.Calcd. for C H CINO C, 61.4; H, 8.8; N, 5.1. Found: C, 61.1; H, 8.3; N, 5.4.

EXAMPLE 2.-2-(2-PYRROLIDINOETHOXY)-1-PHENYL- ETHANOL Sodium, 0.25 g. (0.01 mole), was added in small portions to 92 g. (0.8 mole) of 2-pyrrolidinoethanol while stirring. After solution was complete, the mixture was heated to an internal temperature of and 48 g. (0.4 mole) of styrene oxide added over 1.5 hours. Stirring was continued at this temperature for an additional 4 hours.

0n distillation, 54.8 g. of 2-pyrrolidinoethanol were collected, boiling at 76 at 10 mm. Further distillation of the reaction mixture gave 23.0 g. (41%) of 2-(2-pyrrolidinoethoxy) l-phenylethanol, boiling at -138 at 0.1 mm.

Analysis.Calcd. for C H NO C, 71.5; H, 9.0; N, 6.0. Found: C, 70.9; H, 8.5; N, 5.7.

A hydrochloride, prepared and recrystallized (methyl ethyl ketone), melted at l25130.

Analysis.Calcd. for C H CINO C, 61.9; H, 8.2; N, 5.2. Found: C, 62.1; H, 8.3; N, 5.5.

' EXAMPLE 3 In a similar manner the following alcohols were pre pared and areherein characterized.

B-DIALKY A rno Lrroxr-a-soBsTrTUrnD PHENYL-V- As more specifically illustrative of the preparation of 70 EXAMPLE E the compounds contemplated by this invention, the following specific examples of the preparation of specific compounds contemplated by this invention, will serveto exemplifyjt'he preparation of all compounds, since. allot ETHYL BENZOATE v To a refluxing solution of 4.2 g. (0.03 mole) of benzoyl chloride in 100 ml; of dry benzene was added 7.1 g; (0,03 mole) of 2-(Z-diethylaminoethoxy) lrphenylethae. the" several compounds contemplated will be prepared in. 7 nol over 15 mimlteewhjile. stirringivigorously. Reflux,

EXAMPLE 5.2-(2-DIETHYLAMINOETHOXY)-1-PHENYL- ETHYL P-METHOXYBENZOATE 2-(2-diethylaminoethoxy) -1-phenylethanol, 7.1 g. (0.03 mole), was dissolved in 50 ml. of acetonitrile and 5.6 g. (0.033 mole) of anisoyl chloride added. There was a slight rise in temperature. The reaction mixture was permitted to stand two days at room temperature. After removing the solvent at diminished pressure, the base was prepared as described in Example 4.

On distillation, 2.5 g. of 2-(2-diethylaminoethoxy)-1- phenylethanol was recovered, boiling at 132-134 at 0.4 mm., followed by 3.9 g. of product boiling at 200-2l0 at 0.8 mm. The latter was redistilled to give 2.0 g. boiling at 188-192 at 0.2 mm.

Analysis.--Calcd. for C H NO C, 71.1; H, 7.9; N, 3.8. Found: C, 71.2; H, 7.8; N, 3.8.

EXAMPLE 6.2- (2-DIETHYLAMINOETHOXY) -1-PHENYL- ETHYL CINNAMATE 2-(2-diethylaminoethyl)-1-phenylethyl cinnamate was prepared by the method used in Example 5, starting with 7.1 g. (0.03 mole) of 2-(2-diethylaminoethoxy)-1-phenylethanol, 5.5 g. of cinnamoyl chloride and 50 ml. of acetonitrile. After removal of solvent, the residue was taken up in water, washed with ether and then converted to the base as in Example 4. Distillation yielded a forerun of 2-(2-diethylaminoethoxy)-1-phenylethanol, boiling at 114-116 at 0.18 mm., and then the product was obtained boiling at 192-194 at 0.08 mm.

Analysis.-Calcd. for C H NO C, 75.2; H, 8.0; N, 3.8 Found: C, 74.8; H, 7.9; N, 3.8.

EXAMPLE 7 In a similar manner the following esters have been prepared and characterized.

The new compounds may be used as medicaments, for example, in the form of pharmaceutical preparations which contain the compounds in admixture with a pharmaceutical organic or inorganic solid or liquid carrier 5 suitable for parenteral or topical administration. For making these preparations there are used substances which do not react with the new compound, for example, water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols,

10 petroleum jelly, cholesterol or other carriers known for medicaments.

It is to be understood that it is intended to cover all changes and modifications of the examples of the invention herein chosen for the purpose of illustration which do not constitute departures from the spirit and scope of the invention.

We claim:

1. The basic ester of the formula n-cmcm-owrrr-orr g R/ a R. 5Q

3. The compound R; R, R; R Y Formula B.P., mm

0. Press CH2- H!- H H H2)r- CnHzsNOs -142 0. 4 (CH8):OH CH:- H H Hz):- CnHgrNOl -162 0. 04

CgHr- CgHr- CH; H -(CH:)2 CgzHzsNOs 176-180 0. 2

n C4H9- n C4H9- H H -(CH:): CuHuNO: 161-164 0. 1

-(CH, 4- H H (CH:):- CarHtsNOs 146-150 g 0.05 '-(CH2)e H H (CH)r- CnHaoClNO: CH:- CH:- H H --CH2CHCHs CmHnNO: 132-134 0. 00 CsHs- (33H;- H H CH2CHCH: a: as s -172 0. 02 z r- C: s- H P' P H1)z- CzzHaoNO: 156 0.03 0,11:- C:H5- H O-CHtO- CH1) CHIHIQNO; 178-180 0. 08 CH:- CH: H p-Cl (CH2): CmHnClNOl 15 0. 03

0:11;- CrHr- H p-Cl -(CH:) CnHuClNOa 198-200 0. 6

"The compound was isolated as the hydrochloride. 111.1. 181-190.

T 4'; The compound.

7. The process for preparing a basic ester of the formula R; I R3 ll wherein R and R are members of'the group consisting of lower alkyl groups having a carbon content'C -C4 and the structure wherein R plus R is tctramethylene, R is a member of the group consisting of hydrogen and methyl, R is a member of the group consisting of hydro gen, p-chloro p-methyl, o-methoxy and p-methoxy which comprises condensing, in the presence of catalytic quantities of sodium, an amino alcohol of the formula R R NCH CH DH with a styrene oxide of the formula CH2CHCQH4-Ra separating by fractional distillation the formed fi-dialkylaminoalkoxy-u-phenylethanol of the formula esterifying said phenylethanol' with an aromatic acid chloride of the formula R C H C OCl and isolating said basic ester.

8. The amino alcohol of theformula R1\ Ra N-CHRCHr-O-CHr-CH-Q 4 R2 H wherein R and R are members of the group consisting of lower alkyl groups having a carbon content C -C and the structure wherein R plus R is tetramethylene and R is a member of the group consisting of hydrogen and methyl.

9. The compound 10. The corrrpoundv (mm)rN(cH=)=-0-oHr H- 11. The compound N-cHr-cHr-o-orn-cn-C A References Cited in the file of this patent FOREIGN PATENTS 1,018,070 Germany, Oct 24, 1957 Patent No. 2,92a a45 UNITEl) STATES Flots m OFFICE CERTIFICATE or CORRECTION March 15 1960 Seymour L. Shapiro et al.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below. 7

Column 4 line 6 title of EXAMPLE 1 for "=N-l-PROPYL.

AMINO read N-iPROPYLAMlNO lines 54 to 57 the formula should appear as shown below instead of as in the patent: R1 3 N-Y-o-cn -ca 2 I column 6, lines 20 to 23,, the left-hand portion of the formula should appear as shown below instead of as in the patent:

column 7, line 2 the bond originating from the para position of the top benzene ring shouldhave a CH group attached thereto; line 26 for the "R" substituent shown in the lower benzene ring read R -6 Signed and sealed this 23rd day ofAugust 1960a (SEAL) Attest:

KARL- H. AXLINE ROBERT C, WATSON Attesti'ng Officer Conunissioner of Patents 

1. THE BASIC ESTER OF THE FORMULA
 8. THE AMINO ALCOHOL OF THE FORMULA 